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AJMCtv® Interviews, January 2019
Produced by Samantha DiGrande and Jaime Rosenberg

Clinical: Chronic Lymphocytic Leukemia

Updates from the annual ASH meeting, December 2018.

Ibrutinib Alone Better Than Chemoimmunotherapy as Frontline in Older Patients With CLL

Surabhi Dangi-Garimella, PhD

According to the results of Alliance A041202, an international multicenter phase 3 trial, ibrutinib (Imbruvica) produces superior progression-free survival (PFS) compared with standard chemoimmunotherapy (CIT) in older patients with chronic lymphocytic leukemia (CLL), and adding rituximab (Rituxan) does not improve the ibrutinib response.1 The results were presented as part of the plenary session on December 2, 2018, at the 60th American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California.

Accounting for about 25% to 30% of US leukemia cases, the American Cancer Society reports that nearly 21,000 new cases of CLL were diagnosed last year and the disease was responsible for about 4500 deaths.2

CIT has been the gold standard for patients, with bendamustine plus rituximab (BR) being a standard, more aggressive CIT regimen for patients age 65 or older. The Bruton tyrosine kinase inhibitor ibrutinib was approved by the FDA in 2016 for CLL,3 but it’s only been compared with chlorambucil in this patient population, not with aggressive CIT. Also, the impact of adding rituximab to the ibrutinib treatment has not been evaluated, explained Jennifer A. Woyach, MD, associate professor, The Ohio State University College of Medicine, Columbus.

“Older patients are underrepresented in CLL clinical trials, unless the trial has been specifically designed for them,” Woyach said.

Data from the RESONATE-2 trial presented at the 2017 ASH annual meeting compared treatment-naïve patients receiving ibrutinib as a single agent or chemoimmunotherapy regimens with patients with CLL who were receiving various combination treatments. Based on their results, the authors recommended that single-agent ibrutinib could be used in place of the combination chemotherapy regimens.4

The Alliance A041202 trial has 3 treatment arms—BR (arm 1), ibrutinib alone (arm 2), and ibrutinib plus rituximab (arm 3)—which are designed to determine whether ibrutinib-containing regimens lead to superior PFS compared with CIT in treatment-naïve older patients.5 PFS was defined as the time from randomization to first detection of disease progression or death. Additionally, this study sought to determine if adding rituximab to ibrutinib would prolong PFS over ibrutinib alone, Woyach said. The trial design allowed patients on arm 1 who progressed to cross over to arm 2. Data for the presentation at the ASH meeting were locked on October 4, 2018, Woyach added.

For trial inclusion, patients had to be 65 years or older with previously untreated, symptomatic CLL; creatinine clearance had to be at least 40 mL/min; bilirubin had to be ≤1.5 the upper limit of normal; and patients should have had no significant life-limiting intercurrent illness or need for warfarin treatment. Of the 644 patients who were screened, 547 were randomized 1:1:1 to the 3 arms. Thirty patients in the BR arm crossed over to the ibrutinib-alone arm following analysis.

The median age of trial enrollees was 71 years (range, 65-89) and a majority (67%) were men. High-risk Rai stage (stage III/IV) was detected in 54% of patients, unmethylated Zap-70 in 53%, del(17p) or del(11q) by local fluorescence in situ hybridization analysis in 25%, and complex karyotype in 29%.

PFS was higher in the ibrutinib-alone cohort compared with the ibrutinib-plus-rituximab cohort, Woyach said. In the eligible patient population, at a median follow-up of 24 months, 74%

of patients in arm 1 were alive and progression-free (95% CI, 66%-80%) compared with 87% in arm 2 (95% CI, 81%-92%) and 88% in arm 3 (95% CI, 81%-92%).

No significant differences in PFS were observed in the 2 ibrutinib arms among patients with a complex karyotype, she said. Two-year PFS estimates were 59%, 39%, and 87% in arms 1, 2, and 3, respectively. Overall response rates in the intent-to-treat population were 81%, 93%, and 94%, respectively, and the complete response rates were 26%, 7%, and 12%.

“We did not observe any significant differences in overall survival [OS] among the arms, which might be due to the crossover or the short follow-up time,” Woyach said. She reported that median OS had not been reached for any arm, and OS estimates were 95%, 90%, and 94% for arms 1, 2, and 3, respectively, at a 38-months follow-up.

Adverse events (AEs) were observed at a significantly high rate in this trial. Hematologic AEs were observed in 61%, 41%, and 38% of patients in arms 1, 2, and 3, respectively. Nonhematologic AEs were observed in 63%, 74%, and 74%.

“Hematologic AEs were prevalent in the BR arm while nonhematologic AEs were more common in the ibrutinib arms,” Woyach said. “Unexplained or unwitnessed death over the entire observation period was seen in 2 [1.1%], 7 [3.9%], and 13 [7%] patients in arms 1, 2, and 3 respectively.”

Concluding her presentation, Woyach said that the findings from their trial justify using ibrutinib as a standard-of-care treatment for patients 65 and older and that combining it with rituximab does not improve PFS outcomes. “Clinical trials of this patient population are still of high clinical interest, and the coop- erative group setting remains a reasonable avenue to complete these large studies,” she added.

  1. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus ritux- imab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202. In: Proceedings from the American Society of Hematology; December 1-3, 2018; San Diego, CA. Abstract 6. webprogram/Paper116653.html.
  2. American Cancer Society. Key statistics for chronic lymphocytic leukemia. ACS website. Updated May 10, 2018. Accessed December 2, 2018.
  3. FDA approves Imbruvica (ibrutinib) for the first-line treatment of chronic lymphocytic leukemia [press release]. North Chicago, IL: PR Newswire; March 4, 2016. newdrugs/fda-approves-imbruvica-ibrutinib-first-line-chronic-lymphocytic-leukemia-4353. html. Accessed December 3, 2018.
  4. Dangi-Garimella S. Single-agent ibrutinib promising in MCL and CLL, improves patient well-being. The American Journal of Managed Care® website. cll-improves-patient-well-being. Accessed December 2, 2018.
  5. Rituximab and Bendamustine Hydrochloride, Rituximab and Ibrutinib, or Ibrutinib Alone in Treating Older Patients With Previously Untreated Chronic Lymphocytic Leukemia. clinical- Updated November 2, 2018. Accessed December 2, 2018.

iLLUMINATE: Superior PFS With Ibrutinib–Obinutuzumab Even in High-Risk, Untreated CLL/SLL

Surabhi Dangi-Garimella, PhD

Ibrutinib combined with obinutuzumab had better progression-free survival (PFS) at 30 months than the standard chemo- immunotherapy regimen, chlorambucil plus obinutuzumab, regardless of high-risk genomic features in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) who had never been treated.1 Carol Moreno, MD, presented results from iLLUMINATE December 3, 2018, at the 60th American Society of Hematology Annual Meeting & Exposition, held in San Diego, California.

Ibrutinib is a first-in-class, once-daily inhibitor of Bruton tyrosine kinase and was approved in 20162 in the United States as a single-agent, chemotherapy-free regimen for patients with CLL. The iLLUMINATE trial is a phase 3, open-label, multicenter trial that was designed to test the efficacy of ibrutinib with obinutuzumab versus chlorambucil with obinutuzumab in treatment-naïve patients with CLL and SLL.3 Eligibility criteria included treatment-naïve CLL/SLL and ≥65 years or <65 years with coexisting conditions (Cumulative Illness Rating Scale score >6, creatinine clearance <70 mL/min, and/or del(17p) or TP53 mutation).

One set of patients received 6 cycles of 420-mg ibrutinib once daily, combined with obinutuzumab 1000 mg on days 1/ 2, 8, and 15 of cycle 1, and day 1 of subsequent 28-day cycles. The other set of patients was treated with 6 cycles of chlorambucil, which was 0.5 mg/kg on days 1 and 15 of each 28-day cycle, combined with obinutuzumab, in the same dose and frequency as above. PFS was the primary endpoint, and secondary endpoints included PFS in a high-risk population—del(17p)/TP53 mutation, del(11q), and/or unmutated IGHV—rate of undetectable minimal residual disease, overall response rate (ORR), overall survival (OS), and safety. The trial allowed crossover of patients with confirmed progression in the chlorambucil–obinutuzumab arm to single-agent ibrutinib.

The trial enrolled 229 patients, 113 of whom were randomized to the ibrutinib–obinutuzumab arm and 116 to the chlorambucil– obinutuzumab arm. Median age was 71 years (range, 40-87) and 65% of patients had the above listed high-risk genomic features.

With a median follow-up of 31.3 months, patients who were treated with ibrutinib–obinutuzumab had a significantly better PFS compared with the comparator arm (median not reached [NR] vs 19.0 months; HR, 0.231; 95% CI, 0.145-0.367; P <.0001). At 30 months, the PFS rates were 79% with ibrutinib–obinutuzumab and 31% with chlorambucil–obinutuzumab. These were PFS results as assessed by an independent review committee (IRC), the authors reported.

Investigator (INV)-assessed PFS showed a similar trend for ibrutinib–obinutuzumab versus chlorambucil–obinutuzumab (median PFS NR vs 21.9 months; HR, 0.260; 95% CI, 0.163-0.415; P <.0001). Further, the improvements in PFS seen among patients receiving ibrutinib–obinutuzumab were independent of their genomic status compared with the comparator arm (median NR vs 14.7 months; HR, 0.154; 95% CI, 0.087- 0.270; P <.0001).

Both IRC- and INV-assessed ORR were better for the ibrutinib-obinutuzumab arm. IRC-assessed ORR was 88% with ibrutinib and obinutuzumab versus 73% with the comparator, and INV-assessed ORRs were 91% and 81%, respectively. Similar trends were observed with the IRC-assessed complete response (CR) rate, which was higher with ibrutinib and obinutuzumab (19% vs 8%). INV-assessed CR rates were 41% and 16%, respectively.

The authors report similar 30-month OS rates: 86% in the ibrutinib–obinutuzumab arm and 85% in the chlorambucil and obinutuzumab arm, with 40% of patients randomized to chlorambucil–obinutuzumab receiving single-agent ibrutinib as second-line therapy. Over a median follow-up of 31.3 months, 4% of patients in the ibrutinib–obinutuzumab arm and 44% in the chlorambucil–obinutuzumab arm initiated subsequent therapy.

Adverse Events

The most frequent (≥3%) serious adverse events (AEs) among patients in the ibrutinib–obinutuzumab arm were pneumonia (5%), atrial fibrillation (4%), febrile neutropenia (4%), and pyrexia (4%). The more common serious AEs in the chlorambucil–obinutuzumab were infusion-related reactions (IRRs; 7%), febrile neutropenia (6%), pneumonia (4%), tumor lysis syndrome (4%), and pyrexia (3%). Although no patients discontinued obinutuzumab due to IRRs in the ibrutinib and obinutuzumab arm, 7 patients in the comparator stopped obinutuzumab.

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